2. Academic Validation
  3. Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability

Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability

  • J Med Genet. 2021 Apr;58(4):237-246. doi: 10.1136/jmedgenet-2020-106849.
Arisha Rasheed # 1,  Evren Gumus # 2 3,  Maha Zaki # 4,  Katherine Johnson 5,  Humera Manzoor 1,  Geneva LaForce 5,  Danica Ross 6 7,  Jennifer McEvoy-Venneri 6 7,  Valentina Stanley 7,  Sangmoon Lee 6 7,  Abbir Virani 6 7,  Tawfeg Ben-Omran 8,  Joseph G Gleeson 6 9,  Sadaf Naz # 10,  Ashleigh Schaffer # 11
Affiliations

Affiliations

  • 1 School of Biological Sciences, University of the Punjab Quaid-i-Azam Campus, Lahore, Pakistan.
  • 2 Medical Genetics, Mugla Sitki Kocman University Faculty of Medicine, Mugla, Turkey.
  • 3 Medical Genetics, Harran University Faculty of Medicine, Sanliurfa, Turkey.
  • 4 Clinical Genetic Department, National Research Centre, Cairo, Egypt.
  • 5 Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
  • 6 Rady Children's Institute for Genomic Medicine, San Diego, California, USA.
  • 7 Department of Neuroscience, University of California, San Diego, La Jolla, CA, USA.
  • 8 Clinical and Metabolic Genetics Division, Department of Pediatrics, Weill-Cornell Medical College, Hamad Medical Corporation, Doha, Qatar.
  • 9 Department of Neuroscience and Pediatrics, Howard Hughes Medical Insistute, University of California, San Diego, La Jolla, CA, USA.
  • 10 School of Biological Sciences, University of the Punjab Quaid-i-Azam Campus, Lahore, Pakistan [email protected] [email protected].
  • 11 Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA [email protected] [email protected].
  • # Contributed equally.
PMID: 32439809 DOI: 10.1136/jmedgenet-2020-106849
Abstract

Background: Intellectual disability syndromes (IDSs) with or without developmental delays affect up to 3% of the world population. We sought to clinically and genetically characterise a novel IDS segregating in five unrelated consanguineous families.

Methods: Clinical analyses were performed for eight patients with intellectual disability (ID). Whole-exome sequencing for selected participants followed by Sanger sequencing for all available family members was completed. Identity-by-descent (IBD) mapping was carried out for patients in two Egyptian families harbouring an identical variant. RNA was extracted from blood cells of Turkish participants, followed by cDNA synthesis and Real-Time PCR for TTC5.

Results: Phenotype comparisons of patients revealed shared clinical features of moderate-to-severe ID, corpus callosum agenesis, mild ventriculomegaly, simplified gyral pattern, cerebral atrophy, delayed motor and verbal milestones and hypotonia, presenting with an IDS. Four novel homozygous variants in TTC5: c.629A>G;p.(Tyr210Cys), c.692C>T;p.(Ala231Val), c.787C>T;p.(Arg263Ter) and c.1883C>T;p.(Arg395Ter) were identified in the eight patients from participating families. IBD mapping revealed that c.787C>T;p.(Arg263Ter) is a founder variant in Egypt. Missense variants c.629A>G;p.(Tyr210Cys) and c.692C>T;p.(Ala231Val) disrupt highly conserved residues of TTC5 within the fifth and sixth tetratricopeptide repeat motifs which are required for p300 interaction, while the nonsense variants are predicted to decrease TTC5 expression. Functional analysis of variant c.1883C>T;p.(Arg395Ter) showed reduced TTC5 transcript levels in accordance with nonsense-mediated decay.

Conclusion: Combining our clinical and molecular data with a recent case report, we identify the core and variable clinical features associated with TTC5 loss-of-function variants and reveal the requirement for TTC5 in human brain development and health.

Keywords

developmental; genetics; molecular genetics; neurology.

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